Effector and Memory Anti-Malaria CD8+ Cell Responses

效应器和记忆抗疟疾 CD8 细胞反应

• 批准号: 7727860
• 负责人: FIDEL P ZAVALA
• 金额: $ 51.99万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7727860
• 关键词: Antigen-Presenting Cells; Antigens; Attenuated; Binding; Bite; Bone Marrow; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Adhesion Molecules; Cells; Complex; Culicidae; DNA; Dendritic Cells; Development; Environment; Epitopes; Event; Evolution; Genes; Glycine decarboxylase; Hepatocyte; Homing; Immune; Immune response; Immune system; Immunity; Infection; Integrins; Laboratories; Lead; Liver; Maintenance; Malaria; Mediating; Memory; Methodology; Modeling; Organ; Parasites; Pattern recognition receptor; Peripheral; Plasmodium; Play; Population; Process; Property; Proteins; Recombinants; Research; Role; Site; Skin; Sporozoites; Staging; Subunit Vaccines; System; T memory cell; T-Lymphocyte; Tissues; Toll-like receptors; Transgenic Mice; Transgenic Organisms; Vaccination; Viral Vector; chemokine receptor; design; in vivo; knockout animal; lymph nodes; memory recall; public health relevance; receptor; residence; response; synthetic construct

DESCRIPTION (provided by applicant): CD8+ T cells play a major protective role in immunity to malaria infection by inhibiting the development of liver stages. Vaccination studies using malaria sporozoites, and recombinant viral vectors as well as synthetic constructs such as DNA, have provided important new information regarding the protective role of these T cells. Our recent studies on CD8+ T cell responses against the CS protein of P. yoelii established that when sporozoites are delivered by mosquito bites, the T cell response is induced by dendritic cells (DCs) in skin draining lymph nodes (LN). Primed cells migrate to peripheral organs including the liver, where they develop memory CD8+ populations. Upon challenge these liver resident CD8+ T cells are able to eliminate malaria infection. To protect, T cells have to see antigen in the context of liver parenchymal cells - presumably infected hepatocytes - and need not be re-stimulated by bone-marrow derived DCs. Thus the processes of priming the CD8+ T cell response and eliciting effector function from those cells involve different cellular and molecular interactions. We propose to undertake studies aimed at characterizing some basic aspects of the in vivo CD8+ T cell responses against the liver stages of P. yoelii. These studies aim to define basic features of the key initial interactions that occur between sporozoites, DCs and pattern recognition receptors which lead to the acquisition and presentation of parasite antigen to CD8+ T cells in LN. We also propose studies on liver-resident memory CD8 cells which aim at characterizing the mechanisms that mediate their homing to the liver, at defining their functional properties and evaluating conditions that may modulate the permanence and anti-parasite activity of these memory cells. These studies will be facilitated by the availability of TCR transgenic mice and transgenic parasites expressing model CD8 epitopes developed in my laboratory. These enable us to track CD8 T cells throughout their differentiation in both normal and gene-knockout animals. Finally, we will develop research aimed at studying the functional properties and evolution of memory responses against the P. yoelii CS protein. We will evaluate the fate of these memory cells under continued antigen stimulation which normally occurs due to repeated parasite exposure and antigen persistence. We will study the renewal mechanisms of memory populations and the relationship between different memory cell subsets i.e., those residing in the liver (effector memory and those from lymph nodes (central memory). PUBLIC HEALTH RELEVANCE: The proposal aims at investigating basic features of CD8+ T cell responses against Malaria liver stages. We propose to characterize the role of dendritic cell subsets in induction of this response, the role of adhesion molecule in homing and functional properties of liver-resident anti-Malaria memory T cells and study the mechanisms controlling the evolution and maintenance of protective memory CD8+ T cells.

描述（由申请人提供）：CD8+ T细胞通过抑制肝脏阶段的发展在对疟疾感染的免疫中起主要保护作用。使用疟疾孢子虫和重组病毒载体以及诸如DNA等合成构建体的疫苗接种研究为这些T细胞的保护作用提供了重要的新信息。我们最近关于针对P. yoelii的CS蛋白的CD8+ T细胞反应的研究确定，当蚊子叮咬传递孢子虫时，在皮肤排水淋巴结（LN）中，树突状细胞（DCS）诱导了T细胞反应。底漆细胞迁移到包括肝脏在内的外围器官，在那里它们会发展记忆CD8+种群。在挑战时，这些肝脏常驻CD8+ T细胞能够消除疟疾感染。为了保护，T细胞必须在肝实质细胞（可能感染的肝细胞）的背景下看到抗原，并且不必被骨髓衍生的DC重新刺激。因此，从这些细胞中启动CD8+ T细胞反应和启动效应子功能的过程涉及不同的细胞和分子相互作用。我们建议进行旨在表征体内CD8+ T细胞反应的一些基本方面的研究，以针对P. yoelii的肝脏阶段进行表征。这些研究旨在定义孢子虫，DC和模式识别受体之间发生的关键初始相互作用的基本特征，从而导致LN中寄生虫抗原对CD8+ T细胞的获取和呈现。我们还提出了对肝居民记忆CD8细胞的研究，旨在表征介导其归巢向肝脏的机制，以定义其功能特性并评估可能调节这些记忆细胞的永久性和抗寄生虫活性的条件。这些研究将通过在我的实验室中开发的TCR转基因小鼠和表达模型CD8表位的转基因寄生虫的可用性来促进这些研究。这些使我们能够在正常和基因敲除动物的整个分化中跟踪CD8 T细胞。最后，我们将开发旨在研究针对P. yoelii CS蛋白的功能特性和记忆反应的演变的研究。我们将在持续的抗原刺激下评估这些记忆细胞的命运，这通常是由于反复的寄生虫暴露和抗原持久性而发生的。 We will study the renewal mechanisms of memory populations and the relationship between different memory cell subsets i.e., those residing in the liver (effector memory and those from lymph nodes (central memory). PUBLIC HEALTH RELEVANCE: The proposal aims at investigating basic features of CD8+ T cell responses against Malaria liver stages. We propose to characterize the role of dendritic cell subsets in induction of this response, the role of adhesion molecule in肝居民抗马拉里亚记忆T细胞的归巢和功能特性，并研究控制保护性记忆CD8+ T细胞的演化和维持的机制。